5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one → 5-{[1-(N,N-dimethylglycyl)-6-(ethyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one

HRID 1014461Notes

Reaction equation

Cl[C:2]1[N:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]2=[O:16])=[C:12]([F:17])[CH:11]=[CH:10][CH:9]=3)[C:5]2[CH:18]=[CH:19][N:20]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:4]=2[N:3]=1.[CH3:31][N:32]([CH2:34][C:35]([N:37]1[C:46]2[C:41](=[CH:42][C:43]([O:48][CH2:49][CH3:50])=[C:44]([NH2:47])[CH:45]=2)[CH2:40][CH2:39][CH2:38]1)=[O:36])[CH3:33]>O1CCCC1>[CH3:31][N:32]([CH3:33])[CH2:34][C:35]([N:37]1[C:46]2[C:41](=[CH:42][C:43]([O:48][CH2:49][CH3:50])=[C:44]([NH:47][C:2]3[N:15]4[C:6](=[N:7][C:8]5[C:13]([C:14]4=[O:16])=[C:12]([F:17])[CH:11]=[CH:10][CH:9]=5)[C:5]4[CH:18]=[CH:19][N:20]([S:21]([C:24]5[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=5)(=[O:23])=[O:22])[C:4]=4[N:3]=3)[CH:45]=2)[CH2:40][CH2:39][CH2:38]1)=[O:36]

Participants

Conditions

Temperature: 75 °C

Procedure

A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (550 mg, 1.147 mmol) and 1-[(dimethylamino)acetyl]-6-(ethyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (318 mg, 1.147 mmol) in tetrahydrofuran (30 mL) was stirred at 75° C. in a pressure vessel for 16 hours. All volatiles were removed and the solids were partitioned between dichloromethane and saturated sodiuim bicarbonate. The organic layer was taken to a residue under reduced pressure and the derived solids were triturated with diethyl ether to afford 5-{[1-(N,N-dimethylglycyl)-6-(ethyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (548 mg, 0.801 mmol, 69.8%) as a yellow solid. A solution of 5-{[1-(N,N-dimethylglycyl)-6-(ethyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.548 g, 0.801 mmol) in tetrahydrofuran (50 ml) was treated with methylamine in THF (2.0M) (3.21 ml, 6.41 mmol) and stirred for 16 hours. Celite was added, all volatiles were removed under reduced pressure, and the residue was purified via column chromatography to afford 2-({2-{[1-(N,N-dimethylglycyl)-6-(ethyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (310 mg) The tosylate was dissolved in 1,4-dioxane (8 ml)/2.0N NaOH (aq) (8 ml), added to a microwave vial, and warmed under microwave heating at 120° C. for 12 minutes. The reaction was cooled, diluted with ethyl acetate/saturated sodium chloride (aq), and the organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[1-(N,N-dimethylglycyl)-6-(ethyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.110 g, 0.196 mmol, 24.48%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (s, 1H), 10.10 (s, 1H), 8.47-8.57 (m, 1H), 8.42 (s, 1H), 8.24 (d, J=6.82 Hz, 1H), 7.45 (s, 1H), 7.30-7.42 (m, 1H), 6.99 (d, J=3.01 Hz, 1H), 6.89-6.98 (m, 1H), 6.81 (s, 1H), 6.29 (dd, J=3.41, 1.81 Hz, 1H), 4.03-4.17 (m, 2H), 3.70 (t, J=6.72 Hz, 2H), 3.20 (s, 2H), 2.79 (d, J=4.41 Hz, 3H), 2.61-2.70 (m, 2H), 2.09 (t, J=9.43 Hz, 6H), 1.77-1.92 (m, 2H), 1.37 (t, J=6.82 Hz, 3H). ESIMS (M+H)+=561.

Workup

customAll volatiles were removed
customthe solids were partitioned between dichloromethane and saturated sodiuim bicarbonate
customthe derived solids were triturated with diethyl ether

Sources & evidence

ORD record: ord-1e57b62167144624aae1269963e1492b
Source dataset: uspto-grants-2011_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07981903B2

Reaction notes

Loading…